Although the mechanism to the resolution of diabetes after roux-en-y gastric bypass has yet to be elucidated, the surgical diversion of food from the duodenum with early delivery of nutrients to the jejunum appears to play a central role. Glucose-inhibitory polypeptide (GIP) is an incretin released from the proximal small intestine and enhances the release of insulin from the pancreas in the presense of glucose. We hypothesize that GIP plays a critical role in the resolution of diabetes after roux-en-y gastric bypass. In Specific Aim 1, we hypothesize that removal of chronic stimulation of nutrients after duodenal-jejunal exclusion will result in decreased levels of GIP, an up-regulation of pancreatic GIP receptors and a return of GIP receptor induced insulin secretion in pancreatic islet cells. A modified roux-en-y gastric bypass will be performed in both diabetic and non-diabetic rats. Plasma GIP, insulin, and glucose levels will be assessed for four weeks after surgery. After four weeks, the animals will undergo a lymphatic fistula procedure for evaluation of gastrointestinal lymph for the presense of GIP. The lymph levels will be compared to plasma GIP levels. Following lymphatic sampling, pancreatic islet cells will be harvested for GIP mRNA and protein. Further, islets will be cultured to test if the incretin function of GIP has been restored after duodenal-jejunal exclusion. In Specific Aim 2, we hypothesize that chronic GIP infusion in non-diabetic rats will result in the deterioration of glucose homeostasis by down-regulation of GIP receptor expression and blunting the signaling of GIP induced insulin secretion. Also, we expect that chronic GIP infusion after RYGB in diabetic rats will inhibit the resolution of Type II DM, highlighting the importance of GIP-GIP receptor interaction to the mechanism of resolution of diabetes after RYGB. GIP will be chronically infused via an intraperitoneal implanted pump for four weeks, and the effect of GIP infusion on plasma insulin and glucose will be evaluated. This model will be used in both diabetic and non-diabetic rats before and after gastric bypass. After the four weeks of GIP treatment, the pancreatic islet cells will be harvested and isolated for GIP mRNA and protein expression as well as the effect of GIP stimulation of pancreatic islet cell insulin secretion. PUBLIC HEALTH RELEVANCE: Diabetes is the sixth leading cause of death in the US and 60% of individuals with type II diabetes mellitus are obese. 90% of patients with type II diabetes mellitus have complete resolution of diabetes after roux-en-y gastric bypass, a surgical procedure performed for weight loss in the morbidly obese. Identifying the mechanism for this resolution offers not only the possibility for new drug therapy but also the novel use of surgery as a potential cure for type II diabetes mellitus.